Decreased GABAA receptor binding in the medullary serotonergic system in the sudden infant death syndrome.
γ-Aminobutyric acid (GABA) neurons in the medulla oblongata help regulate homeostasis, in part through interactions with the medullary serotonergic (5-HT) system. Previously, we reported abnormalities in multiple 5-HT markers in the medullary 5-HT system of infants dying from sudden infant death syndrome (SIDS), suggesting that 5-HT dysfunction is involved in its pathogenesis. Here, we tested the hypothesis that markers of GABAA receptors are decreased in the medullary 5-HT system in SIDS cases compared with controls. Using tissue receptor autoradiography with the radioligand H-GABA, we found 25% to 52% reductions in GABAA receptor binding density in 7 of 10 key nuclei sampled of the medullary 5-HT system in the SIDS cases (postconceptional age [PCA] = 51.7 ± 8.3, n = 28) versus age-adjusted controls (PCA = 55.3 ± 13.5, n = 8) (p ≤ 0.04). By Western blotting, there was 46.2% reduction in GABAAα3 subunit levels in the gigantocellularis (component of the medullary 5-HT system) of SIDS cases (PCA = 53.9 ± 8.4, n = 24) versus controls (PCA = 55.3 ± 8.3, n = 8) (56.8% standard in SIDS cases vs 99.35% in controls; p = 0.026). These data suggest that medullary GABAA receptors are abnormal in SIDS infants and that SIDS is a complex disorder of a homeostatic network in the medulla that involves deficits of the GABAergic and 5-HT systems.


Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma: a nested case-control study.
Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. However, human studies, particularly from prospective settings, are lacking. We used a case-control study design nested within a large prospective cohort to assess the association between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG) (reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139 men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and degree of liver dysfunction, were calculated with conditional logistic regression. Antibody response to LPS and flagellin was associated with a statistically significant increase in the risk of hepatocellular carcinoma (highest vs. lowest quartile: RR = 11.76, 95% confidence interval = 1.70-81.40; P trend = 0.021). This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for chronic infection with hepatitis B and C viruses. These novel findings, based on exposures up to several years prior to diagnosis, support a role for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut barrier failure and exposure to bacterial products in liver diseases is warranted.


Sonographic-anatomic correlation and imaging protocol for the kidneys of horses.
Sonographic and anatomic observations were made of the kidneys of 23 Thoroughbreds or Standardbreds. In an in vitro study of 16 horses, precise correlations were established between the gross anatomic features of the kidneys and their sonographic appearance in images obtained in dorsal, sagittal, transverse, and transverse oblique anatomic planes. The renal cortex had a uniformly mottled echogenicity, and the renal medulla was relatively hypoechogenic, compared with the cortex. Acoustic anisotropy was observed in the cortex and medulla of the cranial and caudal extremities of each kidney. The distinctive renal pelvis was seen in the transverse plane as an echogenic pair of diverging lines that lead to the crescent shaped renal crest in the lateral half of the kidney. In images made in the sagittal plane, the renal pelvis was seen as a pair of parallel echogenic lines separated by the moderately echogenic line of the renal crest. The terminal recesses were best seen in the transverse oblique views of each extremity, where they appeared as moderately echogenic lines in the medulla of the cranial and caudal extremities. The interlobar vessels were represented as irregular echogenic lines in the medulla, and the arcuate vessels were seen as echogenic points at the corticomedullary junction. At the hilus, the renal artery or its branches was located cranial to the renal vein, which in turn was cranial to the position of the proximal portion of the ureter. In an in vivo study of 7 horses, sonographic images of the right kidney were obtained in the sagittal, transverse, and transverse oblique anatomic planes in all horses, with the transducer positioned at the 15th, 16th, or 17th intercostal space; images in the dorsal plane were obtained, however, in only 3 of the horses. For the left kidney, sonographic images were obtained in each of the anatomic planes when the transducer was positioned at the 16th or 17th intercostal space or the paralumbar fossa; rectal location of the transducer gave images in the dorsal and sagittal planes. In this study, a routine sonographic imaging protocol, using standard anatomic planes, enabled each kidney to be examined in its entirety. The protocol provided definition of normal renal sonographic anatomic features and may permit a more informed and accurate recognition of renal pathologic change.


Prevalence of potential drug-drug interactions involving antiretroviral drugs in a large Kenyan cohort.
Clinically significant drug-drug interactions (CSDIs) involving antiretrovirals are frequent and under-recognized in developed countries, but data are lacking for developing countries. To investigate the prevalence of CSDIs between antiretrovirals and coadministered drugs, we surveyed prescriptions dispensed in a large HIV clinic in Kenya. Of 1040 consecutive patients screened, 996 were eligible for inclusion. CSDIs were defined as 'major' (capable of causing severe or permanent damage, contraindicated, avoid or not recommended by the manufacturer, or requiring dose modification) or 'moderate' (manufacturers advise caution, or close monitoring, or capable of causing clinical deterioration). A total of 334 patients (33.5%) were at risk for a CSDI, potentially lowering antiretroviral drug concentrations in 120 (12%) patients. Major interactions most frequently involved rifampicin (12.4%, mostly with efavirenz) and azoles (2.7%) whereas moderate interactions were frequently azoles (13%), steroids (11%), and antimalarials (3%). Multivariable analyses suggested that patients at risk for CSDIs had lower CD4 counts (P = 0.006) and baseline weight (P = 0.023) and WHO Stage 3 or 4 disease (P≤0.007). Risk for CSDIs was not associated with particular regimens, although only 116 (11.6%) patients were receiving WHO second line regimens. One in three patients receiving antiretrovirals in our programme were at risk of CSDIs. Strategies need to be urgently developed to avoid important drug interactions, to identify early markers of toxicity and to manage unavoidable interactions safely in order to reduce risk of harm, and to maximize the effectiveness of mass antiretroviral deployment in Africa.


Intravenous Misuse of Methadone, Buprenorphine and Buprenorphine-Naloxone in Patients Under Opioid Maintenance Treatment: A Cross-Sectional Multicentre Study.
The act of intravenous misuse is common in patients under opioid maintenance treatment (OMT), but information on associated factors is still limited. To explore factors associated with (a) intravenous OMT misuse, (b) repeated misuse, (c) emergency room (ER) admission, (d) misuse of different OMT types and (e) concurrent benzodiazepine misuse. We recruited 3,620 patients in 27 addiction units in Italy and collected data on the self-reported rate of intravenous injection of methadone (MET), buprenorphine (BUP), BUP-naloxone (NLX), OMT dosage and type, experience of and reason for misuse, concurrent intravenous benzodiazepine misuse, pattern of -misuse in relation to admission to the addiction unit and ER -admissions because of misuse. According to inclusion/exclusion criteria, 2,585 patients were included. Intravenous misuse of OMT substances was found in 28% of patients with no difference between OMT types and was associated with gender, age, type of previous opioid abuse and intravenous benzodiazepine misuse. Repeated OMT misuse was reported by 20% (i.e., 71% of misusers) of patients and was associated with positive OMT misuse experience and intravenous benzodiazepine misuse. Admission to the ER because of misuse complications was reported by 34% of patients, this outcome being associated with gender, employment, type of previous opioid abuse and intravenous benzodiazepine misuse. OMT dosage was lower than the recommended maintenance dosage. We offered new information on factors associated with intravenous OMT misuse, repeated misuse and ER admission in Italian patients under OMT. Our data indicate that BUP-NLX misuse is not different from that of BUP or MET. Choosing the more expensive BUP-NLX over MET will likely not lead to the expected reduction of the risk of injection misuse of the OMT. Instead of prescribing new and expensive OMT formulations, addiction unit physicians and medical personnel should better focus on patient's features that are associated with a higher likelihood of misuse. Care should be paid to concurrent benzodiazepine and OMT misuse.


Effects of (+)-usnic acid and (+)-usnic acid-liposome on Toxoplasma gondii.
Toxoplasma gondii pathogen is a threat to human health that results in economic burden. Unfortunately, there are very few high-efficiency and low-toxicity drugs for toxoplasmosis in the clinic. (+)-Usnic acid derived from lichen species has been reported to have anti-inflammatory, antibacterial, anti-parasitology, and even anti-cancer activities. Herein, the systematic effect of (+)-usnic acid and (+)-usnic acid-liposome on toxoplasma were studied in vitro and in vivo. The viability of toxoplasma tachyzoite was assayed with trypan blue and Giemsa staining; while the invasive capability of tachyzoite to cardiofibroblasts was detected using Giemsa staining. The survival time of mice and the changes in tachyzoite ultrastructure were studied in vivo. The results showed that (+)-usnic acid inhibited the viability of tachyzoite; pretreatment with (+)-usnic acid significantly decreased the invasion of tachyzoite to cardiofibroblasts in vitro; (+)-usnic acid and (+)-usnic acid-liposome extensively prolonged the survival time of mice about 90.9% and 117%, respectively; and improved the ultrastructural changes of tachyzoite, especially in dense granules, rhoptries, endoplasmic reticulum, mitochondria and other membrane organelles. In summary, these results demonstrate that (+)-usnic acid and (+)-usnic acid-liposome with low toxicity have an inhibitory effect on the viability of toxoplasma tachyzoite, and mainly destructed membrane organelles which are connected with the virulence of toxoplasma. These findings provide the basis for further study and development of usnic acid as a potential agent for treating toxoplasmosis.


BAFF and TACI gene expression are increased in patients with untreated very early rheumatoid arthritis.
B cells play important roles in rheumatoid arthritis (RA). Given the beneficial effect of B cell depletion therapy in RA as well as the observed alterations in B cell subpopulations in this disease, we evaluated whether changes in the expression of genes related to B cell survival and activation were already present in patients with untreated very early RA (VERA; < 6 weeks of disease duration). The expression of a group of B cell-related activation and survival genes was quantified in peripheral blood mononuclear cells from patients with VERA by real-time PCR and compared with untreated early RA (< 1 year), established treated RA, and other untreated early arthritis conditions. Serum B cell-activating factor belonging to the tumor necrosis factor family (BAFF) was quantified by ELISA. BAFF gene expression and serum levels were highest in patients with VERA. The expression of BAFF receptor (BAFF-R) increased with disease progression, while transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) was elevated since the first weeks of RA onset. Paired box 5 gene expression was also increased at all RA stages. Chemokine (C-X-C motif) receptor 5 was elevated only in established RA. No differences were observed in B cell maturation antigen, activation-induced cytidine deaminase, B lymphocyte-induced maturation protein, and B cell lymphoma 2 expression. Disturbances in the expression of B cell-related activation and survival genes, particularly BAFF and TACI, occur from the onset of RA and precede changes in BAFF-R. These alterations can lead to the development of autoreactive B cells from the first weeks of RA onset.


A new genetic model for calcium induced autophagy and ER-stress in Drosophila photoreceptor cells.
Cytoplasmic Ca2+ overload is known to trigger autophagy and ER-stress. Furthermore, ER-stress and autophagy are commonly associated with degenerative pathologies, but their role in disease progression is still a matter of debate, in part, owing to limitations of existing animal model systems. The Drosophila eye is a widely used model system for studying neurodegenerative pathologies. Recently, we characterized the Drosophila protein, Calphotin, as a cytosolic immobile Ca2+ buffer, which participates in Ca2+ homeostasis in Drosophila photoreceptor cells. Exposure of calphotin hypomorph flies to continuous illumination, which induces Ca2+ influx into photoreceptor cells, resulted in severe Ca2+-dependent degeneration. Here we show that this degeneration is autophagy and ER-stress related. Our studies thus provide a new model in which genetic manipulations trigger changes in cellular Ca2+ distribution. This model constitutes a framework for further investigations into the link between cytosolic Ca2+, ER-stress and autophagy in human disorders and diseases.


Myosin VI and its cargo adaptors - linking endocytosis and autophagy.
The coordinated trafficking and tethering of membrane cargo within cells relies on the function of distinct cytoskeletal motors that are targeted to specific subcellular compartments through interactions with protein adaptors and phospholipids. The unique actin motor myosin VI functions at distinct steps during clathrin-mediated endocytosis and the early endocytic pathway - both of which are involved in cargo trafficking and sorting - through interactions with Dab2, GIPC, Tom1 and LMTK2. This multifunctional ability of myosin VI can be attributed to its cargo-binding tail region that contains two protein-protein interaction interfaces, a ubiquitin-binding motif and a phospholipid binding domain. In addition, myosin VI has been shown to be a regulator of the autophagy pathway, because of its ability to link the endocytic and autophagic pathways through interactions with the ESCRT-0 protein Tom1 and the autophagy adaptor proteins T6BP, NDP52 and optineurin. This function has been attributed to facilitating autophagosome maturation and subsequent fusion with the lysosome. Therefore, in this Commentary, we discuss the relationship between myosin VI and the different myosin VI adaptor proteins, particularly with regards to the spatial and temporal regulation that is required for the sorting of cargo at the early endosome, and their impact on autophagy.


Simultaneous Assessment of Urinary and Fecal Volatile Organic Compound Analysis in De Novo Pediatric IBD.
Endoscopic evaluation is mandatory in establishing the diagnosis of pediatric inflammatory bowel disease (IBD), but unfortunately carries a high burden on patients. Volatile organic compounds (VOC) have been proposed as alternative, noninvasive diagnostic biomarkers for IBD. The current study aimed to assess and compare the potential of fecal and urinary VOC as diagnostic biomarkers for pediatric IBD in an intention-to-diagnose cohort. In this cohort study, patients aged 4-17 years, referred to the outpatient clinic of a tertiary referral center under suspicion of IBD, were eligible to participate. The diagnosis was established by endoscopic and histopathologic assessment, participants who did not meet the criteria of IBD were allocated to the control group. Participants were instructed to concurrently collect a fecal and urinary sample prior to bowel lavage. Samples were analyzed by means of gas chromatography-ion mobility spectrometry. In total, five ulcerative colitis patients, five Crohn's disease patients, and ten age and gender matched controls were included. A significant difference was demonstrated for both fecal (p-value, area under the curve; 0.038, 0.73) and urinary (0.028, 0.78) VOC profiles between IBD and controls. Analysis of both fecal and urinary VOC behold equal potential as noninvasive biomarkers for pediatric IBD diagnosis.


Severe dementia. Prevalence and clinical features in a biracial US population.
The purpose of this investigation was to document the prevalence of severe dementia among different racial groups residing in the same community--Copiah County, Mississippi. Both household and institutionalized populations were included. For either sex, the prevalence ratios of all severe dementia and clinically diagnosed severe senile dementia of the Alzheimer's type were at least as large among blacks as among whites. For either race, the corresponding prevalence ratios were greater in females. For each race and sex, the corresponding prevalence ratios increased with advancing age. Finally, in the population studied, approximately 1% of individuals 40 years old or older had severe dementia. This figure increased to 7% for individuals 80 years old or older.


Oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolaemic humans.
Elevated low-density lipoproteins (LDLs) are associated with vascular dysfunction evident in the cutaneous microvasculature. We hypothesized that uncoupled endothelial nitric oxide synthase (NOS3) through upregulated arginase contributes to cutaneous microvascular dysfunction in hyperocholesterolaemic (HC) humans and that a statin intervention would decrease arginase activity. Five microdialysis fibres were placed in the skin of nine normocholesterolaemic (NC: LDL level 95±4 mg dl⁻¹) and nine hypercholesterolaemic (HC: LDL: 177±6 mg dl⁻¹) men and women before and after 3 months of systemic atrovastatin. Sites served as control, NOS inhibited, arginase inhibited, L-arginine supplemented and arginase inhibited plus L-arginine supplemented. Skin blood flow was measured while local skin heating (42°C) induced NO-dependent vasodilatation. L-NAME was infused after the established plateau in all sites to quantify NO-dependent vasodilatation. Data were normalized to maximum cutaneous vascular conductance (CVC(max)). Skin samples were obtained to measure total arginase activity and arginase I and arginase II protein. Vasodilatation was reduced in hyperocholesterolaemic subjects (HC: 76±2 vs. NC: 94±3%CVC(max), P < 0.001) as was NO-dependent vasodilatation (HC: 43±5 vs. NC: 62±4%CVC(max), P < 0.001). The plateau and NO-dependent vasodilatation were augmented in HC with arginase inhibition (92±2, 67±2%CVC(max), P < 0.001), L-arginine (93±2, 71±5%CVC(max), P < 0.001) and combined treatments (94±4, 65±5%CVC(max), P < 0.001) but not in NC. After statin intervention (LDL: 98±5 mg dl⁻¹) there was no longer a difference between control sites (88±4, 61±5%CVC(max)) and localized microdialysis treatment sites (all P > 0.05). Arginase activity and protein were increased in HC skin (P < 0.05 vs. NC) and activity decreased with atrovastatin treatment (P < 0.05). Reduced NOS3 substrate availability through upregulated arginase contributes to cutaneous microvascular dysfunction in hyperocholesterolaemic humans, which is corrected with atorvastatin therapy.


Surgical treatment of a Morgagni hernia causing intermittent gastric outlet obstruction.
A Morgagni hernia is a rare diaphragmatic hernia which develops through a congenital defect in the retrosternal area, usually on the right hand side. Because of its congenital aetiology, Morgagni hernias are rarely considered in the differential diagnosis of gastric outlet obstruction symptoms in adults. We present a patient with an incarcerated Morgagni hernia who presented with gastric outlet obstruction. A 77-year-old woman presented with symptoms and signs of gastric outlet obstruction, dehydration and acute renal impairment. She was treated by fluid resuscitation and nasogastric tube insertion. Radiological imaging showed a Morgagni hernia containing stomach, omentum and colon. This was treated surgically via an abdominal approach and the defect was closed with mesh. The patient recovered well from this procedure and was discharged. We discuss the anatomy, clinical presentation and surgical treatment of this rare diaphragmatic hernia to raise awareness among surgeons and surgical trainees.


Association between childcare movement behaviour compositions with health and development among preschoolers: Finding the optimal combinations of physical activities and sedentary time.
Little is known about how wake-time movement behaviour compositions while in childcare relate to children's health and development. This study aimed to use compositional analysis to examine how childcare movement behaviour compositions were associated with standardised body mass index (zBMI) and physical and psychosocial functioning among children in the preschool setting. A total of 405 preschoolers wore accelerometers during childcare hours to measure their moderate-to-vigorous physical activity (MVPA), light intensity physical activity (LPA) and sedentary time. Compositional regression, isotemporal substitution models, and the "Goldilocks" approach was used to examine how wake-time childcare movement behaviour compositions related to each of the outcomes. Engaging in greater LPA relative to MVPA and sedentary time was associated with higher BMI z-scores, replacing sedentary time or time spent in MVPA with LPA was associated with greater physical functioning, and spending more time in sedentary behaviours relative to overall physical activity was related with greater psychosocial functioning. It is not clear what the optimal wake-time movement behaviour composition while in childcare is for health and development; however, LPA and sedentary time while in childcare may have some benefits. More research is needed to aid the development of childcare-specific guidelines for physical activity and sedentary behaviours.


[Blood management in surgery--an analysis].
The surgeon has a tremendous influence on the usage of blood and blood products. He determines the indication and operative strategy. So the co-operation of anesthetist, intensivist, transfusion specialist, and surgeon is essential to achieve improvement in blood saving. Guidelines of blood saving methods can support the aim of an effective blood management. We analyzed the today's situation of blood saving in surgery and discuss the matter by a questionnaire sent to all surgical institutions of Nordrhein-Westfalen. The data observed cover the results of the Sanguis study from 1994 and the resume that the indication of blood transfusion mostly is not driven by clinical and scientific facts alone. Till today no evidence based data exist on indications for transfusion of blood and blood products. This is required for the next years in order to create changes in the current system of blood saving. The key points to stay within the low range of the number of transfusions are to develop a specific peri-, intra-, and postoperative strategy according to patient, disease, and expected procedure. The surgical aspects are discussed.


Effect of betamethasone on Na-K-ATPase activity and basal and lateral cell membranes in proximal tubular cells during early development.
The mechanism by which betamethasone induces Na-K-ATPase activity in developing tissue was studied in homogenates of proximal tubular cells from 10-day-old rats. A significant increase in Na-K-ATPase activity occurred after 5 micrograms . 100 g-1 . 12 h-1 X 2 beta-methasone and a maximal increase after 15-60 micrograms . 100 g-1 . 12 h-1 X 2. Following a single dose of 60 micrograms . 100 g-1 betamethasone Na-K-ATPase activity increased significantly after 16 h and maximally after 24-30 h. The 16-h time lag suggests that betamethasone does not act only directly on Na-K-ATPase synthesis. Betamethasone 60 micrograms . 100 g-1 increases Na-K-ATPase activity significantly in kidneys in which glomerular filtration rate is reduced by ureteral ligation, but the increase is significantly less pronounced than in kidneys with intact ureters, suggesting that the induction is not mediated only by alterations in sodium supply. Twenty-four hours after 10-60 micrograms . 100 g-1 betamethasone there was no significant increase in glucose-6-phosphatase and Mg-ATPase activity in 10-day-old rats or in Na-K-ATPase activity in 40-day-old rats. The basal and lateral cell membranes of the proximal tubular cells were not significantly increased 24 h after 60 micrograms . 100 g-1 betamethasone. Accordingly, structural development is not a prerequisite for enzymatic differentiation.


Electrophysiological studies in acute organophosphate poisoning.
Electrophysiological studies in suicidal patients with organophosphate poisoning are reported. Patients often developed muscular weakness of variable severity owing to diplorisation block at nicotinic receptors. During such paralysis nerve conduction velocity and distal latencies were normal even in severely paralysed patients. The amplitude of the compound action potential was smaller than in controls and often showed a repetitive response. The amplitude tended to be lower in those more severely affected. On repetitive stimulation there was usually no decrement with three stimuli per second and only occasional decrement at 10 per second. At 30 Hz several cases showed a decrement even in the absence of paralysis. This response to repetitive stimuli is thus quite distinct from that seen in either myasthenia or Eaton Lambert syndrome. On three occasions after poisoning with dichlorovos there was first anticholinesterase insecticide poisoning and later delayed neurotoxicity as seen with triorthocresylphosphate. These cases showed all the features of a severe pure motor axonal degeneration neuropathy.


Personality development: stability and change.
In this review, we evaluate four topics in the study of personality development where discernible progress has been made since 1995 (the last time the area of personality development was reviewed in this series). We (a) evaluate research about the structure of personality in childhood and in adulthood, with special attention to possible developmental changes in the lower-order components of broad traits; (b) summarize new directions in behavioral genetic studies of personality; (c) synthesize evidence from longitudinal studies to pinpoint where and when in the life course personality change is most likely to occur; and (d) document which personality traits influence social relationships, status attainment, and health, and the mechanisms by which these personality effects come about. In each of these four areas, we note gaps and identify priorities for further research.


First report of human myiasis in GoiáS state, Brazil: frequency of different types of myiasis, their various etiological agents, and associated factors.
The objective of this study was to show which species of flies are responsible for human myiasis in the Brazilian state of Goiás and to determine the frequency of cases. Patients at the Clinical Hospital of the Federal University of Goiás (UFG) were examined, and any fly larvae found in their wounds were collected for taxonomic identification. First instar larvae were observed using light microscopy; second and third instars were examined using stereoscopy. The following screwworm flies were observed, in decreasing order of prevalence: Cochliomyia hominivorax, Sarcodexia lambens, Dermatobia hominis, Chrysomya albiceps, Chrysomya megacephala, Lucilia cuprina, and Eristalis tenax. Myiasis was most frequent in the legs in adults, male patients, elderly people, and people of reproductive age. It was lowest in children, females, and patients with neurologic or psychiatric disorders. Frequency was high in patients living in low socioeconomic conditions with poor personal hygiene. Education and sanitation measures are needed to counteract this situation.


Social Buffering as a Tool for Improving Rodent Welfare.
The presence of a conspecific can be calming to some species of animal during stress, a phenomenon known as social buffering. For rodents, social buffering can reduce the perception of and reaction to aversive experiences. With a companion, animals may be less frightened in conditioned fear paradigms, experience faster wound healing, show reduced corticosterone responses to novelty, and become more resilient to everyday stressors like cage-cleaning. Social buffering works in diverse ways across species and life stages. For example, social buffering may rely on specific bonds and interactions between individuals, whereas in other cases, the mere presence of conspecific cues may reduce isolation stress. Social buffering has diverse practical applications for enhancing rodent wellbeing (some of which can be immediately applied, while others need further development via welfare-oriented research). Appropriate social housing will generally increase rodents' abilities to cope with challenges, with affiliative cage mates being the most effective buffers. Thus, when rodents are scheduled to experience distressing research procedures, ensuring that their home lives supply high degrees of affiliative, low stress social contact can be an effective refinement. Furthermore, social buffering research illustrates the stress of acute isolation: stressors experienced outside the cage may thus be less impactful if a companion is present. If a companion cannot be provided for subjects exposed to out-of-cage stressors, odors from unstressed animals can help ameliorate stress, as can proxies such as pieces of synthetic fur. Finally, in cases involving conditioned fear (the learned expectation of harm), newly providing social contact during exposure to negative conditioned stimuli (CS) can modify the CS such that for research rodents repeatedly exposed to aversive stimuli, adding conspecific contact can reduce their conditioned fear. Ultimately, these benefits of social buffering should inspire the use of creative techniques to reduce the impact of stressful procedures on laboratory rodents, so enhancing their welfare.


[Mnestic disorders in tumors of the temporal lobe].
The paper contains some results of a neuropsychological study of memory in 32 patients with tumors of the temporal lobe. The authors distinguished syndromes of disturbed speech memory (mainly--auditory-verbal) in tumors of the medial, posterior and, to a less degree, frontal areas of the left temporal lobe. In tumors of the right temporal lobe changes of memory were less expressed and had prevalently a visual-image character. An involvement into the process of the hyppocampus leads to a model nonspecific drop of short-time memory, while the expansion of the tumor towards the diencephalo-mesencephalic structures--to a formation of the Korsakoff syndrome. The results of the study demonstrate a certain correlation of disturbed memory with degree of emotional changes. It is being assumed that the defect of a retarded reproduction is due to an inertia of the nervous processes.


Loss of post-transcriptional regulation of DNMT3b by microRNAs: a possible molecular mechanism for the hypermethylation defect observed in a subset of breast cancer cell lines.
A hypermethylation defect associated with DNMT hyperactivity and DNMT3b overexpression characterizes a subset of breast cancers and breast cancer cell lines. We analyzed breast cancer cell lines for differential expression of regulatory miRs to determine if loss of miR-mediated post-transcriptional regulation of DNMT3b represents the molecular mechanism that governs the overexpression of DNMT3b that drives the hypermethylation defect in breast cancer. MicroRNAs (miRs) that regulate (miR-29a, miR-29b, miR-29c, miR-148a, miR-148b) or are predicted (miR-26a, miR-26b, miR-203, miR-222) to regulate DNMT3b were examined among 10 hypermethylator and 6 non-hypermethylator breast cancer cell lines. Hypermethylator cell lines express diminished levels of miR-29c, miR-148a, miR-148b, miR-26a, miR-26b, and miR-203 compared to non-hypermethylator cell lines. miR expression patterns correlate inversely with methylation-sensitive gene expression (r=-0.66, p=0.0056) and directly with the methylation status of these genes (r=0.72, p=0.002). To determine the mechanistic role of specific miRs in the dysregulation of DNMT3b among breast cancer cell lines, miR levels were modulated by transfection of pre-miR precursors for miR-148b, miR-26b, and miR-29c into hypermethylator cell lines (Hs578T, HCC1937, SUM185) and transfection of antagomirs directed against miR-148b, miR-26b, and miR-29c into non-hypermethylator cell lines (BT20, MDA-MB-415, MDA-MB-468). Antagomir-mediated knock-down of miR-148b, miR-29c, and miR-26b significantly increased DNMT3b mRNA in non-hypermethylator cell lines, and re-expression of miR-148b, miR-29c, and miR-26b following transfection of pre-miR precursors significantly reduced DNMT3b mRNA in hypermethylator cell lines. These findings strongly suggest that: i) post-transcriptional regulation of DNMT3b is combinatorial, ii) diminished expression of regulatory miRs contributes to DNMT3b overexpression, iii) re-expression of regulatory miRs reduces DNMT3b mRNA levels in hypermethylator breast cancer cell lines, and iv) down-regulation of regulatory miRs increases DNMT3b mRNA levels in non-hypermethylator breast cancer cell lines. In conlcusion, the molecular mechanism governing the DNMT3b-mediated hypermethylation defect in breast cancer cell lines involves the loss of post-transcriptional regulation of DNMT3b by regulatory miRs.


Sparse regression models for unraveling group and individual associations in eQTL mapping.
As a promising tool for dissecting the genetic basis of common diseases, expression quantitative trait loci (eQTL) study has attracted increasing research interest. Traditional eQTL methods focus on testing the associations between individual single-nucleotide polymorphisms (SNPs) and gene expression traits. A major drawback of this approach is that it cannot model the joint effect of a set of SNPs on a set of genes, which may correspond to biological pathways. To alleviate this limitation, in this paper, we propose geQTL, a sparse regression method that can detect both group-wise and individual associations between SNPs and expression traits. geQTL can also correct the effects of potential confounders. Our method employs computationally efficient technique, thus it is able to fulfill large scale studies. Moreover, our method can automatically infer the proper number of group-wise associations. We perform extensive experiments on both simulated datasets and yeast datasets to demonstrate the effectiveness and efficiency of the proposed method. The results show that geQTL can effectively detect both individual and group-wise signals and outperforms the state-of-the-arts by a large margin. This paper well illustrates that decoupling individual and group-wise associations for association mapping is able to improve eQTL mapping accuracy, and inferring individual and group-wise associations.


Prevalence, awareness, treatment and control of hypertension in a general population sample of 26,913 adults in the Greek EPIC study.
Premature mortality from cardiovascular diseases could be prevented by the effective control of hypertension. Nationwide data for the status of hypertension in the adult Greek population are not available. In the context of the Greek component of the European Prospective Investigation into Cancer and nutrition (EPIC), 26 913 volunteers, aged 20-86 years, were recruited from several regions of Greece. Blood pressure measurements were taken by trained physicians and standard interviewing procedures were used to record medical history, and socio-demographic and lifestyle characteristics. The data were modelled through multiple regression. The prevalence of hypertension (based on two arterial blood pressure measurements on a single occasion) is 40.2% for men and 38.9% for women (age-adjusted to the adult Greek population of 2001). In the sample examined, awareness among hypertensives is 54.4%, pharmaceutical treatment among those aware is 83.9%, and effective control among hypertensives is 15.2%. Prevalence of hypertension increases with age and is higher in rural areas and among individuals of lower education. Awareness and control of hypertension is higher among older individuals, among women and among the highly educated. Moreover, awareness of hypertension is higher among rural residents, whereas control of hypertension is more effective among urban residents. In a large sample of the general Greek population, the prevalence of hypertension among men is lower than the average among the EU countries, whereas the corresponding prevalence among women is higher. Awareness and control of hypertension is lower in Greece than in other western countries, making them public health priorities.


Developing national standards for public health emergency preparedness with a limited evidence base.
The paucity of evidence and wide variation among communities creates challenges for developing congressionally mandated national performance standards for public health preparedness. Using countermeasure dispensing as an example, we present an approach for developing standards that balances national uniformity and local flexibility, consistent with the quality of evidence available. We used multiple methods, including a survey of community practices, mathematical modeling, and expert panel discussion. The article presents recommended dispensing standards, along with a general framework that can be used to analyze tradeoffs involved in developing other preparedness standards. Standards can be developed using existing evidence, but would be helped immensely by a stronger evidence base.


Comparing the Signal-to-Noise Ratio Estimates for Event-Related Potentials: A Simulation Study.
Event-related potential (ERP) is one of the commonly used electrophysiologic measures for brain activity with millisecond time resolution, which has been widely applied to psychology and neuroscience research. Conventionally, ERP is obtained by grand-averaging EEG recordings across multiple trials to improve the signal-to-noise ratio (SNR). Reliable quantitative analysis of the amplitude or latency of ERP requires sufficient SNR. Estimating SNR thus offers a criterion for selecting the trial number in designing experiments and the ERP analysis. Unfortunately, most researchers miss assessing SNR, which leads to the reliability of the results being unchecked, particularly under a low SNR. Although a few SNR estimates for ERP have been proposed, their performances have not yet been well compared. As a result, researchers are still left without a guideline quantifying the quality of their ERP signals. An SNR estimate is considered superior if it more successfully differentiates the difference in noises. Using both simulated and actual ERP components, in this study, we aimed to compare the performances of four SNR estimates. The area under the curve (AUC) was computed from the receiver operating characteristics (ROC) curves to quantify the performances of the SNR estimates in Task I: classifying ERP and spontaneous EEG and Task II: classifying the ERP with different levels of noises. Our results showed that the SNR estimate by calculating the ratio of the highest amplitude in the ERPs to the standard deviation in the baseline time interval (SNRMaidhof) was outstanding in Task I. While the SNR estimate by dividing the mean root square of the signal by the variance of the baseline (SNRM&P) was the best SNR estimate in Task II. These results provided a guideline for assessing the quality of the ERP, excluding experimental subjects, or designing the number of required trials before the quantitative analysis.Clinical Relevance- This study provides the rules of thumb for quantifying the ERP data quality, screening the subjects and designing the number of trials in ERP experiments.


Disorder-Driven Density and Spin Self-Ordering of a Bose-Einstein Condensate in a Cavity.
We study spatial spin and density self-ordering of a two-component Bose-Einstein condensate via collective Raman scattering into a linear cavity mode. The onset of the Dicke superradiance phase transition is marked by a simultaneous appearance of a crystalline density order and a spin-wave order. The latter spontaneously breaks the discrete Z_{2} symmetry between even and odd sites of the cavity optical potential. Moreover, in the superradiant state the continuous U(1) symmetry of the relative phase of the two condensate wave functions is explicitly broken by the cavity-induced position-dependent Raman coupling with a zero spatial average. Thus, the spatially averaged relative condensate phase is locked at either π/2 or -π/2. This continuous symmetry breaking and relative condensate phase locking by a zero-average Raman field can be considered as a generic order-by-disorder process similar to the random-field-induced order in the two-dimensional classical ferromagnetic XY spin model. However, the seed of the random field in our model stems from quantum fluctuations in the cavity field and is a dynamical entity affected by self-ordering. The spectra of elementary excitations exhibit the typical mode softening at the superradiance threshold.


Androgenetic Alopecia: Relationship to Anthropometric Indices, Blood Pressure and Life-Style Habits.
The association of androgenetic alopecia (AGA) with cardiovascular risk factors including hypertension, smoking and high body mass index (BMI) has been investigated in several studies. However, the results are discrepant. The aim of the present study was to evaluate the association of AGA with anthropometrics, blood pressure and lifestyle habits. In this case-control study, 256 men with AGA and 256 age-matched healthy controls were evaluated. Systolic and diastolic blood pressures, as well as anthropometric indices were measured. Data on lifestyle habits including smoking, hookah use and alcohol consumption were also collected. Patients with AGA had significantly lower BMI and lower waist to hip ratio as compared to controls (p = 0.012 and p = 0.002, respectively). Other anthropometrics as well as mean systolic and diastolic blood pressures were not significantly different between the two groups. There was no significant difference between patients and controls in terms of lifestyle habits. Patients with severe AGA (Norwood-Hamilton classification type IV-VII) had significantly higher systolic and diastolic blood pressures as compared to those with mild to moderate AGA (Norwood-Hamilton classification type II, III), but the mean age of the former group was also significantly higher (p < 0.001). In contrast to some previous studies, our findings did not show a significant association between certain cardiovascular risk factors (such as hypertension and smoking) and AGA. Although lower BMI and lower waist to hip ratio were observed in the patient group, these values were within normal limits and therefore not biologically significant.


Xylella and Xanthomonas Mobil'omics.
The gamma-proteobacterium Xanthomonadales groups two closely related genera of plant pathogens, Xanthomonas and Xylella. Whole genome sequencing and comparative analyses disclosed a high degree of identity and co-linearity of the chromosome backbone between species and strains. Differences observed are usually clustered into genomic islands, most of which are delimited by genetic mobile elements. Focus is given in this paper to describe which groups of mobile elements are found and what is the relative contribution of these elements to Xanthomonas and Xylella genomes. Insertion sequence (IS) elements have invaded the Xanthomonas genome several times, whereas Xylella is rich in phage-related regions. Also, different plasmids are found inhabiting the bacterial cells studied here. Altogether, these results suggest that the integrative elements such as phages and transposable elements as well as the episomal plasmids are important drivers of the genome evolution of this important group of plant pathogens.


New Techniques and Agents in the Adjuvant Therapy of Pancreatic Cancer.
Pancreatic ductal adenocarcinoma represents a major oncological challenge. Despite improvements in surgical techniques, long-term survival after resection is poor, with few patients surviving after 5 years. Until recently, there have been no large randomized trials of adjuvant therapy in pancreatic ductal adenocarcinoma. However, major trials such as the European Study Group for Pancreatic Cancer (ESPAC-1) and ESPAC-3 trials have set new standards for patient recruitment and development in this field. Adjuvant therapy has the potential to improve both patient survival and quality of life after curative resection. Currently, the best treatment is with 5-fluorouracil with folinic acid, but in the light of ongoing clinical trials, this may be supplanted by gemcitabine as the treatment of choice. Chemoradiotherapy does not appear to be beneficial in the adjuvant setting, but trials of a wide variety of other techniques and agents in the treatment of advanced disease are being undertaken and some of these will almost certainly be extended into the adjuvant setting in time. Great progress has been made in the adjuvant treatment of pancreatic cancer in the past 10 years and similar advances are likely over the next decade.


In-vitro anti-microbial susceptibility of clinical isolates of pathogenic bacteria to ten antibiotics including phosphomycin.
The minimum inhibitory concentration (MIC) of ten antibiotics was determined for various bacterial pathogens isolated from clinical specimens in a Lagos hospital. The in-vitro activity of penicillin and tetracycline was not very impressive and a similarity was noticed in the resistance patterns of these two antibiotics, while the activity in vitro of the relatively more toxic aminoglycosides and chloramphenicol was high for Gram-negative rods. Ceftazidime demonstrated the highest activity in vitro against all pathogens studied. Cefoxitin, cefuroxime and phosphomycin demonstrated an impressive activity in vitro. Clindamycin was very active against strains of Staphylococcus aureus. beta-lactamase production amongst these strains was studied and the clinical significance of this and their MIC results are discussed.


Gene 1.7 of bacteriophage T7 confers sensitivity of phage growth to dideoxythymidine.
Bacteriophage T7 DNA polymerase efficiently incorporates dideoxynucleotides into DNA, resulting in chain termination. Dideoxythymidine (ddT) present in the medium at levels not toxic to Escherichia coli inhibits phage T7. We isolated 95 T7 phage mutants that were resistant to ddT. All contained a mutation in T7 gene 1.7, a nonessential gene of unknown function. When gene 1.7 was expressed from a plasmid, T7 phage resistant to ddT still arose; analysis of 36 of these mutants revealed that all had a single mutation in gene 5, which encodes T7 DNA polymerase. This mutation changes tyrosine-526 to phenylalanine, which is known to increase dramatically the ability of T7 DNA polymerase to discriminate against dideoxynucleotides. DNA synthesis in cells infected with wild-type T7 phage was inhibited by ddT, suggesting that it resulted in chain termination of DNA synthesis in the presence of gene 1.7 protein. Overexpression of gene 1.7 from a plasmid rendered E. coli cells sensitive to ddT, indicating that no other T7 proteins are required to confer sensitivity to ddT.


MyCites: a proposal to mark and report inaccurate citations in scholarly publications.
Inaccurate citations are erroneous quotations or instances of paraphrasing of previously published material that mislead readers about the claims of the cited source. They are often unaddressed due to underreporting, the inability of peer reviewers and editors to detect them, and editors' reluctance to publish corrections about them. In this paper, we propose a new tool that could be used to tackle their circulation. We provide a review of available data about inaccurate citations and analytically explore current ways of reporting and dealing with these inaccuracies. Consequently, we make a distinction between publication (i.e., first occurrence) and circulation (i.e., reuse) of inaccurate citations. Sloppy reading of published items, literature ambiguity and insufficient quality control in the editorial process are identified as factors that contribute to the publication of inaccurate citations. However, reiteration or copy-pasting without checking the validity of citations, paralleled with lack of resources/motivation to report/correct inaccurate citations contribute to their circulation. We propose the development of an online annotation tool called "MyCites" as means with which to mark and map inaccurate citations. This tool allows ORCID users to annotate citations and alert authors (of the cited and citing articles) and also editors of journals where inaccurate citations are published. Each marked citation would travel with the digital version of the document (persistent identifiers) and be visible on websites that host peer-reviewed articles (journals' websites, Pubmed, etc.). In the future development of MyCites, challenges such as the conditions of correct/incorrect-ness and parties that should adjudicate that, and, the issue of dealing with incorrect reports need to be addressed.


A linear method for the curve fitting of multiexponentials.
Two single-pass methods for fitting multiexponentials to experimental data are described. These methods rely on the construction of a matrix whose characteristic polynomial is used to determine the rates of decay. In the first method, which we call the multiple-delay method, the matrix is constructed using time delays of the experimental data. This method is fast and highly accurate even if the experimental signal contains exponential components with similar rates of decay. In the second method, which we call the successive-integral method, the matrix is constructed using integrals of the experimental data. This procedure yields good results for noisy signals and is a generalization of the method of Martin et al. ((1993) J. Neurosci. Methods, 51: 135-146). In addition, a particular instability of the multiexponential curve fitting problem is identified and a method for overcoming this instability is given.


The enigmatic nature of altruism in organ transplantation: a cross-cultural study of transplant physicians' views on altruism.
Although altruism is a key principle in our current organ donation and transplantation system, the meanings and implications of the term have been widely debated. Recently, a new type of living organ donation--anonymous and non-directed, also called living altruistic donation (LAD)--has brought the issue into sharper focus. Transplant physicians' views on altruism might influence their attitudes and actions toward living altruistic donors. This study aimed to explore such views among transplant physicians in France and Quebec. A total of 27 French and 19 Quebec transplant physicians participated in individual, semi-structured interviews between October 2004 and December 2005. The majority of these participants associated altruism with gratuitousness and saw altruistic acts as multiple and varied, ranging from showing consideration to saving a person's life. The transplant physicians' discourses on altruism were quite diverse, leading us to question the relevance of the concept in organ transplantation and the appropriateness of the term "living altruistic donation."


Microglial pannexin-1 channel activation is a spinal determinant of joint pain.
Chronic joint pain such as mechanical allodynia is the most debilitating symptom of arthritis, yet effective therapies are lacking. We identify the pannexin-1 (Panx1) channel as a therapeutic target for alleviating mechanical allodynia, a cardinal sign of arthritis. In rats, joint pain caused by intra-articular injection of monosodium iodoacetate (MIA) was associated with spinal adenosine 5'-triphosphate (ATP) release and a microglia-specific up-regulation of P2X7 receptors (P2X7Rs). Blockade of P2X7R or ablation of spinal microglia prevented and reversed mechanical allodynia. P2X7Rs drive Panx1 channel activation, and in rats with mechanical allodynia, Panx1 function was increased in spinal microglia. Specifically, microglial Panx1-mediated release of the proinflammatory cytokine interleukin-1β (IL-1β) induced mechanical allodynia in the MIA-injected hindlimb. Intrathecal administration of the Panx1-blocking peptide 10panx suppressed the aberrant discharge of spinal laminae I-II neurons evoked by innocuous mechanical hindpaw stimulation in arthritic rats. Furthermore, mice with a microglia-specific genetic deletion of Panx1 were protected from developing mechanical allodynia. Treatment with probenecid, a clinically used broad-spectrum Panx1 blocker, resulted in a striking attenuation of MIA-induced mechanical allodynia and normalized responses in the dynamic weight-bearing test, without affecting acute nociception. Probenecid reversal of mechanical allodynia was also observed in rats 13 weeks after anterior cruciate ligament transection, a model of posttraumatic osteoarthritis. Thus, Panx1-targeted therapy is a new mechanistic approach for alleviating joint pain.


Noise reduction of image sequences using motion compensation and signal decomposition.
In this paper, a new spatio-temporal filtering method for removing noise from image sequences is proposed. This method combines the use of motion compensation and signal decomposition to account for the effects of object motion. Because of object motion, image sequences are temporally nonstationary, which requires the use of adaptive filters. By motion compensating the sequence prior to filtering, nonstationarities, i.e., parts of the signal that are momentarily not stationary, can be reduced significantly. However, since not all nonstationarities can be accounted for by motion, a motion-compensated signal still contains nonstationarities. An adaptive algorithm based on order statistics is described that decomposes the motion-compensated signal into a noise-free nonstationary part and a noisy stationary part. An RLS filter is then used to filter the noise from the stationary signal. Our new method is experimentally compared with various noise filtering approaches from literature.


Comparison of coastal phytoplankton composition estimated from the V4 and V9 regions of the 18S rRNA gene with a focus on photosynthetic groups and especially Chlorophyta.
We compared the composition of eukaryotic communities using two genetic markers (18S rRNA V4 and V9 regions) at 27 sites sampled during Ocean Sampling Day 2014, with a focus on photosynthetic groups and, more specifically green algae (Chlorophyta). Globally, the V4 and V9 regions of the 18S rRNA gene provided similar images of alpha diversity and ecological patterns. However, V9 provided 20% more OTUs built at 97% identity than V4. 34% of the genera were found with both markers and, of the remnant, 22% were found only with V4 and 44% only with V9. For photosynthetic groups, V4 and V9 performed equally well to describe global communities at different taxonomic levels from the division to the genus and provided similar Chlorophyta distribution patterns. However, at lower taxonomic level, the V9 dataset failed for example to describe the diversity of Dolichomastigales (Chlorophyta, Mamiellophyceae) emphasizing the lack of V9 sequences for this group and the importance of the reference database for metabarcode analysis. We conclude that in order to address questions regarding specific groups (e.g., a given genus), it is necessary to choose the marker based not only on the genetic divergence within this group but also on the existence of reference sequences in databases.


Myodegeneration and suspected selenium/vitamin E deficiency in horses.
The clinical, macroscopic, and microscopic features of 10 isolated cases of myodegeneration in foals were compared. Low values for selenium and vitamin E content were found in the hay and oats from one breeding stable. Serum selenium concentrations in mares at this stable were also low. Creatinine phosphokinase and serum glutamic oxaloacetic transaminase activities were increased in 2 young foals at this stable; in 1 of these foals, both enzymatic activities were markedly reduced after treatment with vitamin E and selenium. Nutritional myodegeneration was suggested as a diagnosis in this stable, on the basis of the histologic findings, feed analyses, serum selenium values, response to treatment, and enzymatic determinations. Nine other isolated cases of nutritional myodegeneration were tentatively diagnosed on the basis of macroscopic and microscopic findings and the young age of the animal. The gross lesions included pale areas in the myocardium and skeletal muscle masses. Histologically, lesions were characterized by fragmentation and hyaline and granular changes in swollen muscle fibers in widely distributed skeletal muscle masses.


Synthesis and Polymerization of an ortho-para-Substituted Tetraalkoxy [2.2]Paracyclophane-1,9-diene.
This contribution describes the synthesis of an unsymmetrical substituted tetraalkoxy[2.2]paracyclophane-1,9-diene comprised of an ortho-substituted and a para-substituted dioctyloxybenzene. (Sp)-4,5,12,15-tetraoctyloxy-[2.2]paracyclophane-1,9-diene ((Sp)-pCpd) and (Rp)-4,5,13,16-tetraoctyloxy-[2.2]paracyclophane-1,9-diene ((Rp)-pCpd) are formed as planar chiral enantiomers. Unlike other tetraalkoxy-substituted pCpds that form as diastereomers, both the (Sp)-pCpd and the (Rp)-pCpd can be polymerized via ring-opening metathesis polymerization (ROMP) using Grubbs' third generation initiator (G3) as it is achiral. Living ROMP afford copolymers featuring alternating cis,trans-poly(p-phenylenevinylene)s (PPV)s. The polymers' unique, blue-shifted optical properties are due to the alkoxy-substitution in the polymer's backbone and the resulting materials could be photoisomerized to the all-trans polymer. This strategy affords tetraalkoxy-pCpd monomers in high yields for the polymerization of soluble PPVs with low or narrow dispersities.


Intestinal parasites among young children in the interior of Guyana.
Intestinal parasites contribute greatly to morbidity in developing countries. While there have been several studies of the problem in the Caribbean, including the implementation of control programmes, this has not been done for Guyana. The aim of this study was to determine the prevalence of intestinal parasites among young children in a town located in the interior of Guyana. Eighty-five children under the age of 12 years were studied prospectively for intestinal parasites in Mahdia, Guyana. Stool samples were transported in formalin to the Department of Microbiology, The University of the West Indies, Jamaica, for analysis using the formalin-ether concentration and Ziehl-Neelsen techniques. Data on age and gender of the children were recorded on field data sheets. At least one intestinal parasite was detected in 43.5% (37/85) of the children studied and multiple parasitic infections were recorded in 21.2% (18/85). The most common intestinal helminth parasite was hookworm (28.2%; 24/85), followed by Ascaris lumbricoides (18.8%; 16/85) and then Trichuris trichuria (14.1%; 12/85). Among the protozoan infections Giardia lamblia was detected in 10.5% (9/85) of the study population while Entamoeba histolytica appeared rarely. All stool samples were negative for Cryptosporidium and other intestinal Coccidia. There was no predilection for gender with any of the parasites. The pattern of distribution of worms in this area of Guyana was unlike that seen in other studies. Hookworm infection was the most common among the children and a large proportion had multiple infections. The study established the occurrence and prevalence of a number of intestinal parasites in the population of Guyana. This sets the stage for the design and implementation of more detailed epidemiological studies.


Blood Pressure and Arterial Stiffness in Kenyan Adolescents With α+Thalassemia.
Recent studies have discovered that α-globin is expressed in blood vessel walls where it plays a role in regulating vascular tone. We tested the hypothesis that blood pressure (BP) might differ between normal individuals and those with α+thalassemia, in whom the production of α-globin is reduced. The study was conducted in Nairobi, Kenya, among 938 adolescents aged 11 to 17 years. Twenty-four-hour ambulatory BP monitoring and arterial stiffness measurements were performed using an arteriograph device. We genotyped for α+thalassemia by polymerase chain reaction. Complete data for analysis were available for 623 subjects; 223 (36%) were heterozygous (-α/αα) and 47 (8%) were homozygous (-α/-α) for α+thalassemia whereas the remaining 353 (55%) were normal (αα/αα). Mean 24-hour systolic BP ±SD was 118±12 mm Hg in αα/αα, 117±11 mm Hg in -α/αα, and 118±11 mm Hg in -α/-α subjects, respectively. Mean 24-hour diastolic BP ±SD in these groups was 64±8, 63±7, and 65±8 mm Hg, respectively. Mean pulse wave velocity (PWV)±SD was 7±0.8, 7±0.8, and 7±0.7 ms-1, respectively. No differences were observed in PWV and any of the 24-hour ambulatory BP monitoring-derived measures between those with and without α+thalassemia. These data suggest that the presence of α+thalassemia does not affect BP and/or arterial stiffness in Kenyan adolescents.


Predictive modeling and in vivo assessment of cerebral blood flow in the management of complex cerebral aneurysms.
Cerebral aneurysms are weakened blood vessel dilatations that can result in spontaneous, devastating hemorrhage events. Aneurysm treatment aims to reduce hemorrhage events, and strategies for complex aneurysms often require surgical bypass or endovascular stenting for blood flow diversion. Interventions that divert blood flow from their normal circulation patterns have the potential to result in unintentional ischemia. Recent developments in computational modeling and in vivo assessment of hemodynamics for cerebral aneurysm treatment have entered into clinical practice. Herein, we review how these techniques are currently utilized to improve risk stratification and treatment planning.


Valproate, bipolar disorder and polycystic ovarian syndrome.
Persons with bipolar disorder are often overweight and cluster risk factors for cardiovascular disease. Some antibipolar agents adversely impact upon weight and the lipid milieu. Recent data suggest that valproic acid, a commonly prescribed mood stabilizer, may be associated with polycystic ovarian syndrome (PCOS). This adverse event has not been systematically studied in bipolar disorder. Thirty-eight female subjects, aged 18-50 years, meeting DSM-IV criteria for bipolar I or II disorder, in any phase of illness were evaluated. Eighteen females received valproate (sodium valproate and valproic acid) and 20 females received lithium. Patients completed questions regarding their menstrual, reproductive and medical histories. During the follicular phase they were assessed for weight, body mass index (BMI kg/m2), and changes in the reproductive endocrine milieu that included morning estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex-hormone binding globulin (SHBG), androstenedione, dehydroepiandrosterone-sulfate (DHEAS), testosterone, free testosterone, prolactin and thyroid-stimulating hormone (TSH). The blood was also analyzed for fasting metabolic parameters which included total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), insulin, glycosylated hemoglobin (HbA1C), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding-protein 1 (IGFBP-1), fasting blood glucose and morning leptin. Nine (50%) of the valproate-treated females had menstrual abnormalities versus three (15%) of the lithium-treated females (p < 0.05). Valproate-treated females had significantly higher levels of follicular phase androgen concentrations than lithium-treated females (p < 0.05). Nine (50%) of females who were overweight (BMI > or = 25 kg/m2) and with a history of menstrual irregularities also exhibited laboratory evidence of hyperandrogenism (p < 0.05). Persons receiving valproate exhibited significant increases in fasting biochemical parameters suggestive of an adverse metabolic syndrome (p < 0.05). Leptin levels were significantly elevated in the valproate-treated females (p < 0.05). In this pilot, open-label cross-sectional study, valproate-treated females exhibited higher rates of menstrual abnormalities and biochemical evidence of both hyperandrogenism and adverse metabolic parameters when compared with lithium-treated females. These preliminary data suggest that valproate may, in some predisposed females, adversely impact upon the reproductive endocrine milieu and result in aspects of the metabolic syndrome.


Sleep timing, chronotype, mood, and behavior at an Arctic latitude (69° N).
Daylight is an important zeitgeber for entraining the circadian rhythm to a 24 h clock cycle, especially within the Polar circle, which has long Polar nights several months each year. Phase delays in sleep timing may occur, but the mean shift is normally small. However, the individual variation in phase shifts is large, implicating moderating factors. Here we examined the role of several self-regulatory variables (mood and fatigue, behavioral habits, and psychological self-regulation) as moderators of seasonality in sleep timing and chronotype. A sample of 162 young adults (76% females; mean age: females 23.4 years, males 24.3 years) participated in a prospective study across three seasons (September, December, March) in Tromsø/Norway at 69°39′N Sleep diary and sleep/health-related questionnaire data were collected at each time-point. Sleep timing and chronotype were delayed during the dark period (December) compared with brighter photoperiods (September and March). Comparable effects were observed for insomnia, fatigue, mood (depression and anxiety), subjective health complaints, physical activity, and school-related stress. Most importantly, depression and fatigue moderated the degree of seasonal shifting in sleep timing, whereas the other self-regulation indicators did not (ie eating habits, physical activity, and psychological self-regulation). Seasonality in sleep timing and chronotype was confirmed, and it seems that depressive symptoms during the dark period exacerbate phase-shifting problems for people living in sub-Arctic regions.


Micronutrient Analysis of Gluten-Free Products: Their Low Content Is Not Involved in Gluten-Free Diet Imbalance in a Cohort of Celiac Children and Adolescent.
Data about the nutritional composition of gluten-free products (GFP) are still limited. Most studies are based on ingredient and nutrition information described on the food label. However, analytical determination is considered the gold standard for compositional analysis of food. Micronutrient analytical content differences were observed in a selection of GF breads, flakes and pasta, when compared with their respective gluten-containing counterparts. In general terms, lower iron, piridoxin, riboflavin, thiamin, niacin, folate, manganese and vitamin B5 can be underlined. Variations in biotin and vitamin E content differed among groups. In order to clarify the potential contribution of the GFP to the gluten-free diet's (GFD) micronutrient shortages, analytical data were used to evaluate GFD in a cohort of celiac children and adolescent. Participants did not reach recommendations for vitamin A, vitamin E, folic acid, vitamin D, biotin, iodine, and copper. It does not seem that the lower micronutrient content of the analyzed GFP groups contributed to the micronutrient deficits detected in GFD in this cohort, whose diet was not balanced. Nevertheless, GFP fortification for folate and biotin is proposed to prevent the deficiencies observed in GFD, at least in the case of pediatric celiac disease.


General anaesthesia during caesarean sections: implications for the mother, foetus, anaesthetist and obstetrician.
A general anaesthetic is usually given for an emergency caesarean section (Category 1), where there is imminent threat to the mother or foetus. There are many risks in performing a general anaesthetic. The aim of this review is to highlight the effects and risks to the mother and foetus of each step of a general anaesthetic. Anaesthetic techniques are changing, and the traditional mantra of using a general anaesthetic for an emergency caesarean sections is being challenged. There are also multiple potential risks of a general anaesthetic that are being better defined. This ranges from awareness during surgery, through to foetal and maternal risks of complications. This review will outline the different stages of a general anaesthetic and highlight the risks. This summary will allow a better understanding of anaesthetic risks. This will allow obstetricians to have a more informed conversation with an anaesthetist as to form of anaesthetic required (general anaesthetic versus spinal or epidural top-up). The review will also allow obstetricians to give more informed consent to mothers and be aware of the postoperative risks.


Diverse effects of natural antioxidants on cyclosporin cytotoxicity in rat renal tubular cells.
As is well known, the use of the immunosuppressive drug cyclosporin A (CsA) is partially restricted by its nephrotoxic effects, which include early changes in haemodynamics followed by irreversible injuries to the renal tubules. Although the mechanisms responsible for these side effects are poorly understood, an involvement of reactive oxygen species (ROS) has been suggested. In this study, we selected three natural antioxidants, resveratrol, hydroxytyrosol and vitamin E, on the basis of their scavenging capabilities, and tested their protective effects against CsA toxicity. Immortalized rat tubular cells (RPTc) were used as the model system. Cell viability was checked with trypan blue assay, and free radical formation was measured using the fluorescent probe 2,7-dichlorofluorescein (DCF). We evaluated several oxidative stress parameters, including phospholipid peroxidation products, glutathione levels and oxygenase expression. Incubation of RPTc with 25 muM CsA induced a significant decrease in cell viability paralleled by intracellular ROS formation and alterations in lipid peroxidation. There was also an imbalance of glutathione redox state as well as upregulation of heme oxygenase-1 (HO-1). The three antioxidants, at micromolar concentration, quantitatively prevented the ROS-activated DCF fluorescent signal and membrane lipid peroxidation. Both hydroxytyrosol and resveratrol strengthened the CsA induction of HO-1 expression. Moreover, vitamin E and resveratrol counteracted CsA-induced changes in the glutathione redox state via different mechanisms, whereas hydroxytyrosol was completely ineffective. Similarly, CsA-dependent nephrotoxicity was prevented by vitamin E, while resveratrol only exerted partial protection, and hydroxytyrosol showed no protective effects. Our results indicate that the diverse cytoprotective effects of the antioxidants tested in these studies were not directly related to their scavenging capabilities. These findings confirm a key role for glutathione in protecting cells from CsA-induced adverse effects and do not support a direct link between CsA-mediated ROS generation and adverse renal effects.


Calcium butyrate: Anti-inflammatory effect on experimental colitis in rats and antitumor properties.
Butyric acid is a physiological component of the colonic environment that possesses anti-inflammatory and antitumor properties, among others. However, little is known regarding its effects following direct application on the colonic surface. This study was conducted to investigate the topical anti-inflammatory effect of calcium butyrate in chemically-induced colitis in rats and to evaluate its antitumor properties in vivo and in vitro. The anti-inflammatory activity of calcium butyrate was evaluated in dinitrobenzene sulfonic acid-induced colitis in rats, following intracolonic instillation for 6 consecutive days and its in vivo antitumor activity was evaluated in F344 rats with the azoxymethane (AOM)-induced aberrant crypt foci (AFC) test, following intracolonic instillation for 4 weeks. The in vitro antiproliferative activity was assessed by incubation for 48 h with the HT29, SW620 and HCT116 intestinal tumour cell lines to evaluate the rate of 3H-thymidine uptake. In dinitrobenzene-induced colitis, the intracolonic instillation of calcium butyrate completely prevented body weight reduction in the animals and counteracted the local noxious effects of the irritant by reducing colon edema (-22.7%, P=0.048) and the area of mucosal damage (-48%, P=0.045). In the AOM-induced AFC test, the intracolonic instillation of calcium butyrate significantly reduced the number of AFC in the entire colon (-22.7%, P<0.05). Calcium butyrate, following incubation with the HT29, SW620 and HCT116 tumour cell lines, induced a significant antiproliferative, dose-dependent effect (P=0.046 to P=0.002) in all three strains, as measured by the reduction in 3H-thymidine uptake. Calcium butyrate directly applied to the mucosa of the rat colon was able to ameliorate colonic inflammation, suggesting a possible beneficial role in the treatment of inflammatory colon diseases. Moreover, calcium butyrate exhibited notable antitumor effects in vivo and in vitro; however, their clinical relevance requires confirmation by additional clinical investigations.


[Effect of ischemia and rotenone on lipid and adenine nucleotide levels and functional activity of heart mitochondria].
Myocardial mitochondria (MCh), isolated with rotenone (MCh + RO) and in absence of rotenone (MCh - RO), were studied in rabbits with ischemia (0.5 hr autolysis) and in controls. Content of acyl-CoA was increased by 50%, linoleic acid - by 49% and lysophosphatidyl choline - by 37% in MCh + RO of control animals as compared with the MCh - RO preparation. In the MCh + RO preparation from rabbits with ischemia content of acyl-CoA was increased by 62%, while concentration of free fatty acids (FFA) and phospholipids was similar to those of the MCh - RO preparation. After isolation of mitochondria with rotenone composition of adenine nucleotides was distinctly altered. Content of ATP was decreased by 27% in mitochondria of both ischemic and control animals, although total amount of adenine nucleotides was decreased only slightly. As shown by estimation of succinate oxidation and membrane potential rotenone did not affect the mitochondrial respiration. In mitochondria of ischemic rabbits concentrations of FFA and lysophosphatidyl choline were increased, whereas content of ATP, total amount of adenine nucleotides, the rate of succinate oxidation and membrane potential were decreased. The method developed, isolation of mitochondria with rotenone, may be used in studies of the role of acyl-CoA in energy metabolism of cells.


Age related increase in impairment across the life course: the use of Zomba curves to estimate assistive technology needs in Malawi.
Global population growth and increasing longevity means that the need for Assistive Technology (AT) will continue to increase. The level of unmet need for AT is greatest in low-income settings. The aim of this study is to identify age-related increase in impairment and to estimate the AT needs. We analysed secondary data from the 2018 Malawi Population and Housing Census (MPHC) based on the Washington Group on Disability Statistics (WG) short-set of questions. Out of the 1,556,670 persons with one or more functional limitations or disabilities identified in the census, self-reported difficulties in all domains were markedly higher from age 40 and above. The proportion reporting one functional limitation is higher compared to two or more limitations, but at age 78-80 the proportion reporting two or more functional limitations increased above those reporting one functional limitation. Although 60.9% (60.7-61.0) and 63.5% (63.3-63.6) of those who reported difficulty in seeing and hearing were using glasses and hearing aids respectively, the estimated total need for glasses and hearing aids in this group was 98.9% (98.0-99.0) and 98.4% (98.3-98.5) respectively. The unmet need for glasses and hearing aids were therefore 38.1% and 34.9% respectively. The differential slope of impairment curves against age is a guide to the increasing demand for AT across the life course and across different domains of functioning. Country specific analysis of impairment across age and domains is essential to understand and plan for the growing need for AT globally.IMPLICATIONS FOR REHABILITATIONIt is important to estimate and plan for impairment across life course to address the age-related increase in impairment and the increasing need for AT with age.The Zomba curves show the cumulative nature of impairment with age and the need for age and need specific provision of AT across the life course through proactive policy level actions.The significant high unmet need for glasses and hearing aids attests to similar need for other assistive products and the need for setting specific interventions to address needs of affected persons.The differential slope of impairment curves against age is a guide to the differing and increasing demand for assistive technology across the life course and across different domains of functioning.


A Comparative Study of the Predictive Values of Urinary Acute Kidney Injury Markers Angiogenin and Kidney Injury Molecule 1 for the Outcomes of Kidney Allografts.
Whether injury-related molecules in urines of individuals with ischemia-reperfusion injury (IRI) are independent predictors of graft outcomes and provide additional information compared with usual risk factors remains to be established. We explored a cohort of 244 kidney transplant recipients who systematically had a urine collection 10 days after transplantation. The injury-related markers kidney injury molecule-1 (KIM-1) and angiogenin (ANG) levels in urines were measured. We determined the prognostic values of these markers on graft outcomes. Urinary KIM-1 and ANG concentrations were strongly correlated to each other and were significantly and independently associated with cold ischemia time, delayed graft function, and plasma creatinine 10 days after transplantation, indicating that these markers reflect the severity of IRI. However, urinary ANG and KIM-1 were not predictive of histological changes on protocol biopsies performed 3 and 12 months after transplantation. Finally, urinary ANG and urinary KIM-1 were not associated with graft survival. Together, our results indicate that, in a cohort of 244 kidney transplant recipients, urinary ANG and KIM-1 levels in a single measurement 10 days after transplantation reflect the severity of IRI after kidney transplantation, but are neither independent predictors of renal function, histological changes and graft survival.


Multitasking of the piRNA Silencing Machinery: Targeting Transposable Elements and Foreign Genes in the Bdelloid Rotifer Adineta vaga.
RNA-mediated silencing processes play a key role in silencing of transposable elements, especially in the germ line, where piwi-interacting RNAs (piRNAs) are responsible for suppressing transposon mobility and maintaining genome integrity. We previously reported that the genome of Adineta vaga, the first sequenced representative of the phylum Rotifera (class Bdelloidea), is characterized by massive levels of horizontal gene transfer, by unusually low transposon content, and by highly diversified RNA-mediated silencing machinery. Here, we investigate genome-wide distribution of pi-like small RNAs, which in A. vaga are 25-31 nucleotides in length and have a strong 5'-uridine bias, while lacking ping-pong amplification signatures. In agreement with expectations, 71% of mapped reads corresponded to annotated transposons, with 93% of these reads being in the antisense orientation. Unexpectedly, a significant fraction of piRNAs originate from predicted coding regions corresponding to genes of putatively foreign origin. The distribution of piRNAs across foreign genes is not biased toward 3'-UTRs, instead resembling transposons in uniform distribution pattern throughout the gene body, and in predominantly antisense orientation. We also find that genes with small RNA coverage, including a number of genes of metazoan origin, are characterized by higher occurrence of telomeric repeats in the surrounding genomic regions, and by higher density of transposons in the vicinity, which have the potential to promote antisense transcription. Our findings highlight the complex interplay between RNA-based silencing processes and acquisition of genes at the genome periphery, which can result either in their loss or eventual domestication and integration into the host genome.


A Blinded Comparative Study of Four Commercially Available LEDs and a Laser Light Curing Device.
This study determined the effectiveness of five light-curing units (LCUs; four light-emitting diode [LED] and one laser) used on different settings to photo-activate four conventional resin-based composites (RBCs). A total of 108 RBC specimens were photo-activated in a white Delrin mold representing a mesial-occlusal-distal (MOD) class II restoration in a molar tooth. The proximal boxes were 5 mm deep, and the mesial-distal length was 12 mm. Immediately after photo-curing, the RBC specimens were immersed in a solvent to remove the uncured materials, after which they were photographed and deidentified. A Research Electronic Data Capture survey was created using these images and sent to respondents who blindly assessed the ability of the various LCUs to photo-cure the MOD restorations. There were significant differences in how the five curing lights had cured RBCs. One-way analysis of variance (ANOVA), pairwise t-test, Welch's one-way ANOVA, and Kruskal-Wallis rank test in the blinded survey data showed significant differences between the LED curing lights used for two 10-second cures and the laser curing light used for 1 second, and LED lights at lower settings. There was a significant difference in how the curing lights could photo-cure the RBCs used in this study. The laser curing light used for 1 second produced the worst results in all four RBCs. When used for 1 second, the laser curing device does not photo-cure conventional RBC materials as well as the LED curing lights used for 10 seconds.


Recombinant cellular model system for human muscle-type nicotinic acetylcholine receptor α12β1δε.
The human muscle-type nicotinic acetylcholine receptor α12β1δε (nAChR) is a complex transmembrane receptor needed for drug screening for disorders like congenital myasthenic syndromes and multiple pterygium syndrome. Until today, most models are still using the nAChR from Torpedo californica electric ray. A simple reproducible cellular system expressing functional human muscle-type nAChR is still missing. This study addressed this issue and further tested the hypothesis that different chaperones, both biological and chemical, and posttranslational modification supporting substances as well as hypothermic incubation are able to increase the nAChR yield. Therefore, Gibson cloning was used to generate transfer plasmids carrying the sequence of nAChR or chosen biological chaperones to support the nAChR folding in the cellular host. Viral transduction was used for stable integration of these transgenes in Chinese hamster ovary cells (CHO). Proteins were detected with Western blot, in-cell and on-cell Western, and the function of the receptor with voltage clamp analysis. We show that the internalization of nAChR into plasma membranes was sufficient for detection and function. Additional transgenic overexpression of biological chaperones did result in a reduced nAChR expression. Chemical chaperones, posttranslational modification supporting substances, and hypothermic conditions are well-suited supporting applications to increase the protein levels of different subunits. This study presents a stable and functional cell line that expresses human muscle-type nAChR and yields can be further increased using the chemical chaperone nicotine without affecting cell viability. The simplified access to this model system should enable numerous applications beyond drug development. Graphical abstract created with http://biorender.com.


A randomized trial of Chinese herbal medicines for the treatment of symptomatic hepatitis C.
Many patients with the hepatitis C virus (HCV) cannot be successfully treated with interferon-based regimens. Chinese herbal medicines have been widely prescribed for HCV in Asia, and many infected patients in the United States have used these agents. However, data to support the efficacy of these medications are limited and, to our knowledge, no published trials have been conducted in a US population. In a double-blinded design, 45 patients with HCV and fatigue were randomized to receive a combination of Chinese herbal medications or a matched placebo for 12 weeks. The main outcome measures were changes in health-related quality of life using the role physical and vitality scale scores from the validated Hepatitis Quality of Life Questionnaire and alanine aminotransferase levels. In addition, other Hepatitis Quality of Life Questionnaire variables, HCV load, and adverse effects were monitored. In patients with HCV, the herbal medications had no effect on any quality-of-life variables, as measured by the Hepatitis Quality of Life Questionnaire. In addition, no significant changes in alanine aminotransferase or serum HCV RNA levels were noted. No significant adverse effects were observed. In this study, a regimen of Chinese herbal medicines did not improve quality of life, liver chemistry results, or viral load in a cohort of patients with HCV. Patients and practitioners should remain cautious about the use of herbal medicines for HCV, because studies have not shown a clear benefit of these agents.


Theoretical study of aromatic hydroxylation of the [Cu2(H-XYL)O2]2+ complex mediated by a side-on peroxo dicopper core and Cu-ligand effects.
In this work, the aromatic hydroxylation mechanism of the [Cu2(H-XYL)O2]2+ complex mediated by a peroxo dicopper core and Cu-ligand effects are investigated by using hybrid density functional theory (DFT) and the broken symmetry B3LYP method. Based on the calculated free-energy profiles, we proposed two available mechanisms. The first reaction steps of both mechanisms involve concerted O-O bond cleavage and C-O bond formation and the second step involves the Wagner-Meerwein rearrangement of the substrate by a [1,2] H shift (HA shift from CA to CC) or (HA shift from CA to OA) across the phenyl ring to form stable dienone intermediates, and this is followed by the protonation of bridging oxygen atoms to produce the final hydroxylated dicopper(ii) product. The HA shift from CA to CC mechanism is the energetically most favorable, in which the first reaction step is the rate-limiting reaction, with a calculated free-energy barrier of 19.0 kcal mol-1 and a deuterium kinetic isotope effect of 1.0, in agreement with experimental observations. The calculation also shows that the reaction started from the P-type species of [Cu2(H-XYL)O2]2+ which is capable of mediating the direct hydroxylation of aromatic substrates without the intermediacy of an O-type species. Finally, we designed some new complexes with different Cu-ligands and found the complex that computationally possesses a higher activity in mediating the hydroxylation of the ligand based aromatic substrate; here, Cu loses a pyridyl ligand donor by dissociation, compared to the [Cu2(H-XYL)O2]2+ complex.


Involvement of the Galbeta1 - 3GalNAcbeta structure in the recognition of apoptotic bodies by THP-1 cells.
A specific apoptotic glycosylation pattern may play an assistant or even a causative role in phagocytosis of apoptotic bodies. To elucidate the role of macrophages in lectin-mediated phagocytosis, an experimental system was used, where monocyte-derived THP-1 cells engulf the apoptotic bodies from the melanoma cell line MELJUSO. A flow cytometry assay was performed to reveal lectin expression and quantify the phagocytosis of apoptotic bodies. Taking into account that siglecs, a mannose receptor and galectins expressed on macrophages could be involved in engulfment of apoptotic bodies we studied their potential expression on THP-1 cells by means of polyacrylamide glycoconjugates. A strong binding of the cells to siglec ligands (3'SiaLac, 6'SiaLac, [Neu5Acalpha2-8]2) and galectin ligands (LacNAc, GalNAcbeta1 - 4GlcNAc, Galbeta1 - 3GalNAcbeta and asialoGM1) was observed. To reveal the corresponding targets on apoptotic bodies, the carbohydrate pattern of MELJUSO cells was analyzed. The apoptotic membrane was characterized by a high level of glycans terminated by galactose or sialic acid. To study lectin-mediated phagocytosis of apoptotic bodies by THP-1 cells, an inhibitory phagocytosis assay was performed. Binding of Galbeta1 - 3GalNAc- or LacNAc-specific reagents (lectins and antibodies) to apoptotic bodies abolished their engulfment by the THP-1 cells whereas blocking of Neu5Acalpha2 - 6 or Neu5Acalpha2 - 3 sites by the corresponding lectins was not effective. Furthermore, Galbeta1 - 3GalNAcbeta-PAA or asialoGM1-PAA binding to the THP-1 cells decreased phagocytosis, whereas two other potent THP-1-binding probes, LacNAc-PAA and GalNAcbeta1 - 4GlcNAc-PAA did not inhibit phagocytosis. Thus, Galbeta1 - 3GalNAcbeta-terminated chains represented on the apoptotic bodies but not the other tested galectin ligands appear to be a target for THP-1 cells.


Bromodomain Proteins Epigenetically Regulate the Mitotically Associated lncRNA MANCR in Triple Negative Breast Cancer Cells.
Long non-coding RNA (lncRNA)-mediated control of gene expression contributes to regulation of biological processes that include proliferation and phenotype, as well as compromised expression of genes that are functionally linked to cancer initiation and tumor progression. lncRNAs have emerged as novel targets and biomarkers in breast cancer. We have shown that mitotically associated lncRNA MANCR is expressed in triple-negative breast cancer (TNBC) cells and that it serves a critical role in promoting genome stability and survival in aggressive breast cancer cells. Using an siRNA strategy, we selectively depleted BRD2, BRD3, and BRD4, singly and in combination, to establish which bromodomain proteins regulate MANCR expression in TNBC cells. Our findings were confirmed by using in situ hybridization combined with immunofluorescence analysis that revealed BRD4, either alone or with BRD2 and BRD3, can support MANCR regulation of TNBC cells. Here we provide evidence for MANCR-responsive epigenetic control of super enhancers by histone modifications that are required for gene transcription to support cell survival and expression of the epithelial tumor phenotype in triple negative breast cancer cells.


Elimination of Pasteurella pneumotropica from a mouse barrier facility by using a modified enrofloxacin treatment regimen.
Multiple NOD. Cg-Prkdc(scid)Il2rg(tm1Wjl)Tg(HLA-A2.1)Enge/Sz (NSG/A2) transgenic mice maintained in a mouse barrier facility were submitted for necropsy to determine the cause of facial alopecia, tachypnea, dyspnea, and sudden death. Pneumonia and soft-tissue abscesses were observed, and Pasteurella pneumotropica biotype Jawetz was consistently isolated from the upper respiratory tract, lung, and abscesses. Epidemiologic investigation within the facility revealed presence of this pathogen in mice generated or rederived by the intramural Genetically Engineered Mouse Model (GEMM) Core but not in mice procured from several approved commercial vendors. Epidemiologic data suggested the infection originated from female or vasectomized male ND4 mice obtained from a commercial vendor and then comingled by the GEMM Core to induce pseudopregnancy in female mice for embryo implantation. Enrofloxacin delivered in drinking water (85 mg/kg body weight daily) for 14 d was sufficient to clear bacterial infection in normal, breeding, and immune-deficient mice without the need to change the antibiotic water source. This modified treatment regimen was administered to 2400 cages of mice to eradicate Pasteurella pneumotropica from the facility. Follow-up PCR testing for P. pneumotropica biotype Jawetz remained uniformly negative at 2, 6, 12, and 52 wk after treatment in multiple strains of mice that were originally infected. Together, these data indicate that enrofloxacin can eradicate P. pneumotropica from infected mice in a less labor-intensive approach that does not require breeding cessation and that is easily adaptable to the standard biweekly cage change schedule for individually ventilated cages.


Translating cholesterol guidelines into primary care practice: a multimodal cluster randomized trial.
PURPOSE We wanted to determine whether an intervention based on patient activation and a physician decision support tool was more effective than usual care for improving adherence to National Cholesterol Education Program guidelines. METHODS A 1-year cluster randomized controlled trial was performed using 30 primary care practices (4,105 patients) in southeastern New England. The main outcome was the percentage of patients screened for hyperlipidemia and treated to their low-density lipoprotein (LDL) and non-high-density lipoprotein (HDL) cholesterol goals. RESULTS After 1 year of intervention, both randomized practice groups improved screening (89% screened), and 74% of patients in both groups were at their LDL and non-HDL cholesterol goals (P <.001). Using intent-to-treat analysis, we found no statistically significant differences between practice groups in screening or percentage of patients who achieved LDL and non-HDL cholesterol goals. Post hoc analysis showed practices who made high use of the patient activation kiosk were more likely to have patients screened (odds ratio [OR] = 2.54; 95% confidence interval [CI], 1.97-3.27) compared with those who made infrequent or no use. Additionally, physicians who made high use of decision support tools were more likely to have their patients at their LDL cholesterol goals (OR = 1.27; 95% CI, 1.07-1.50) and non-HDL goals (OR = 1.23; 95% CI, 1.04-1.46) than low-use or no-use physicians. CONCLUSION This study showed null results with the intent-to-treat analysis regarding the benefits of a patient activation and a decision support tool in improving cholesterol management in primary care practices. Post hoc analysis showed a potential benefit in practices that used the e-health tools more frequently in screening and management of dyslipidemia. Further research on how to incorporate and increase adoption of user-friendly, patient-centered e-health tools to improve screening and management of chronic diseases and their risk factors is warranted.


Targeting vessels to treat hepatocellular carcinoma.
The process of blood vessel proliferation, known as angiogenesis, is essential during embryonic development and organogenesis. In adult life, it participates in normal tissue repair, wound healing, and cyclical growth of the corpus luteum and the endometrium. Crucial as it is, angiogenesis can become pathological, and abnormal angiogenesis contributes to the pathogenesis of inflammatory and neoplasic diseases. The present review highlights the evidence for the role of angiogenesis in HCC (hepatocellular carcinoma) and discusses the increasing importance of inhibitors of angiogenesis in HCC therapy.